CASP1 (human) — curation notes

Provenance note: Provider deep research was unavailable for this gene (Falcon returned
402 Payment Required; Perplexity not configured). This notes file is my own literature
synthesis, written from the cached publications in publications/ and the UniProt record
(CASP1-uniprot.txt), and replaces the usual *-deep-research-<provider>.md file. Every
assertion carries inline provenance as [PMID:NNN "quote"]. No PMID is cited from memory;
each cited title was checked against the cached publications/PMID_*.md record.

Identity and architecture

CASP1 (P29466), interleukin-1β converting enzyme (ICE), is the founding inflammatory
caspase. It is synthesized as an inactive zymogen (pro-caspase-1) with an N-terminal CARD
(residues 1–91), a large catalytic subunit p20 (120–297), an interdomain linker (298–316),
and a small subunit p10 (317–404); catalytic residues are His237 and Cys285
(UniProt feature table; CASP1-uniprot.txt). The active enzyme is a heterotetramer of two
antiparallel p20/p10 heterodimers PMID:8044845. It is a cysteine-dependent,
Asp-specific protease (clan CD) with a preferred cleavage sequence Tyr-Val-Ala-Asp↓
(EC 3.4.22.36; UniProt CATALYTIC ACTIVITY). It was first cloned as the IL-1β-converting
enzyme PMID:1373520 and purified from monocytes as a heterodimeric cysteine protease
PMID:1574116. Five alternatively spliced
isoforms (alpha–epsilon) exist; delta and epsilon are catalytically/apoptotically inactive,
and epsilon can act as a dominant-negative by dimerizing with the p20 subunit
PMID:7876192.

Core function 1 — cysteine protease activity (effector of the inflammasome)

CASP1 is the effector protease of canonical inflammasomes. Its activity and the heterodimeric
protease identity are repeatedly established PMID:1574116, and it is the catalytic output of
the inflammasome platform PMID:12191486. Activation is by proximity-induced autoproteolysis: ASC nucleates
CARD filaments of caspase-1 PMID:24630722, and the caspase-1 CARD itself polymerizes into a
filament whose structure has been solved PMID:27043298.
Interdomain-linker autoprocessing is required for full catalytic activity and for pyroptosis
PMID:32051255.

Core function 2 — maturation of IL-1β and IL-18 (cytokine precursor processing)

The defining physiological substrates are the precursors of IL-1β and IL-18. CASP1 cleaves
pro-IL-1β at Asp116-Ala117 to the mature 17.5 kDa cytokine PMID:2787508, and cleaves pro-IL-18
at Asp36-Tyr37 to generate the bioactive 18 kDa species PMID:9334240. A naturally
occurring Δexon-3 pro-IL-18 isoform is resistant to caspase-1 processing yet still binds the
enzyme PMID:15326478. This is cytokine precursor
processing (GO:0140447) / signaling receptor ligand precursor processing (GO:0140448), the
central role captured by UniProt [CASP1-uniprot.txt FUNCTION "cleaving other proteins, such
as the precursors of the inflammatory cytokines interleukin-1 beta (IL1B) and interleukin 18
(IL18)"].

Core function 3 — GSDMD cleavage and pyroptosis

CASP1 cleaves gasdermin-D (GSDMD) in the interdomain linker, releasing the pore-forming
N-terminal fragment that executes pyroptosis PMID:26375003. GSDMD is
required for IL-1β release and pyroptosis but not for IL-1β maturation itself
PMID:26611636. Recognition of GSDMD is not driven solely by the tetrapeptide
cleavage-site sequence but by an exosite on autoprocessed caspase-1 that binds the GSDMD
C-terminal domain [PMID:32109412 "the β sheet organizes a hydrophobic GSDMD-binding interface
that is only possible for p10-form caspase-4/11 ... Crystal structure of caspase-1-GSDMD-C
complex shows a similar GSDMD-recognition mode"; PMID:32553275 "This 'exosite' interface
endows an additional function for the GSDMD C-terminal domain as a caspase-recruitment module"].
This maps to pyroptotic inflammatory response (GO:0070269) / pyroptotic cell death.

Inflammasome complex membership

CASP1 is the shared effector of NLRP1, NLRP3, NLRC4/IPAF, and AIM2 inflammasomes, recruited
through its CARD either directly (NLRC4/IPAF, CARD8) or via the ASC adaptor (NLRP3, AIM2,
pyrin). Specific complex memberships are well supported:
- NLRP1 inflammasome [PMID:12191486 "comprises caspase-1, caspase-5, Pycard/Asc, and NALP1";
PMID:17349957 "we have reconstituted the NALP1 inflammasome"].
- NLRP3 inflammasome PMID:15030775.
- NLRC4/IPAF inflammasome PMID:11390368.
- AIM2 inflammasome [PMID:19158675 "AIM2 recognizes cytosolic dsDNA and forms a
caspase-1-activating inflammasome with ASC"; PMID:19158676 "AIM2 ... caspase-1"].
- Canonical inflammasome PMID:16037825.

Regulators binding the CARD (basis of many "protein binding" rows)

A family of CARD-only proteins binds the caspase-1 prodomain/CARD and inhibits activation:
COP/CARD16 PMID:11432859, pseudo-ICE/COP and ICEBERG/CARD18
[PMID:11536016 "Pseudo-ICE and ICEBERG interact physically with caspase-1 and block ...
secretion of interleukin-1beta"; PMID:11051551 "ICEBERG ... inhibits generation of IL-1beta
by interacting with caspase-1 and preventing its association with RIP2"], INCA/CARD17
PMID:15383541, and CARD8 PMID:11821383. INCA caps the caspase-1 CARD
filament PMID:27043298.
SERPINB1 restrains caspase-1 CARD oligomerization PMID:30692621.
MEFV/pyrin interacts via both p10 and p20 subunits PMID:16785446. These are CARD-mediated
protein-protein interactions; where a specific function underlies them, CARD domain binding
(GO:0050700) is the informative molecular-function term.

Other substrates / functions (literature-supported, mostly non-core)

• Autoprocessing: generates the active p20/p10 enzyme [PMID:1574116; PMID:32051255] —
  protein autoprocessing (GO:0016540), under proteolysis, the substrate-is-the-enzyme case.
• Caspase-7 activation during bacterial infection → PARP1 cleavage and NF-κB target gene
  expression PMID:22464733.
• cGAS cleavage dampens DNA-virus type-I IFN responses PMID:28314590.
• Sphingosine kinase 2 (SPHK2) cleavage during apoptosis PMID:20197547.
• ZNFX1 cleavage in a feed-forward NLRP3 loop PMID:39333773.
• Unconventional (leaderless) protein secretion PMID:18329368.
• Eicosanoid "storm" downstream of NLRC4 inflammasome in vivo PMID:22902502 — a downstream physiological
  consequence, not a direct CASP1 enzymatic step.
• Apoptosis / neurodegeneration contexts: PARP cleavage by ICE at high enzyme concentration
  PMID:7642516, tau cleavage by multiple caspases including caspase-1 in vitro
  PMID:12888622, caspase-1 activation in
  Huntington's disease models PMID:10353249. These establish apoptotic activity for
  overexpressed/high-dose enzyme and roles in disease models, but IL-1β/IL-18/GSDMD processing
  and pyroptosis are the physiological core.

Localization

CASP1 is a cytoplasmic/cytosolic enzyme active in the cytosol; a fraction localizes to the
plasma membrane [PMID:20197547 FUNCTION/SUBCELLULAR LOCATION in UniProt: Cytoplasm; Cell
membrane]. Cytosol is the compartment where the inflammasome assembles and where CASP1 is
active.

Review decisions summary (rationale for actions)

• MF cysteine-type endopeptidase activity (GO:0004197): core — ACCEPT (many IDA + IBA).
• endopeptidase activity (GO:0004175, IDA PMID:24548080): generalization of the specific
  cysteine-type activity; MODIFY to GO:0004197.
• cysteine-type peptidase activity (GO:0008234, IEA): too general; MODIFY to GO:0004197.
• protein binding (GO:0005515): uninformative bare term; REMOVE (many of the interactions
  are real CARD-mediated regulator interactions captured by GO:0050700 / complex terms).
• CARD domain binding (GO:0050700): ACCEPT — informative, the mechanism of recruitment.
• identical protein binding (GO:0042802): ACCEPT/KEEP — CASP1 homodimerization/filament
  (p20/p10 tetramer, CARD filament) is real.
• kinase binding (GO:0019900, RIP2/RICK): KEEP_AS_NON_CORE — real CARD-CARD interaction with
  RIP2 but not the core function.
• cytokine binding (GO:0019955, PMID:15030775): pro-IL-18 binding is documented; KEEP_AS_NON_CORE.
• enzyme binding (GO:0019899, IEA): too generic; MODIFY toward kinase/CARD binding or REMOVE
  (IEA bare); treat as over-general → MARK_AS_OVER_ANNOTATED/REMOVE of the IEA.
• Complex terms (GO:0061702, GO:0072558/9, GO:0072557, GO:0097169, GO:0032991): ACCEPT the
  specific inflammasome complexes; the AIM2 IBA/IDA/IPI and NLRP3/NLRP1/IPAF rows are sound.
• protease inhibitor complex (GO:0097179, IMP PMID:11432859): this describes COP, the
  inhibitor; caspase-1 is the protease being inhibited, so being "part_of" a protease
  inhibitor complex is defensible (enzyme+inhibitor heterodimer) — KEEP_AS_NON_CORE.
• Cytokine processing: cytokine precursor processing (GO:0140447), signaling receptor ligand precursor processing (GO:0140448), protein maturation (GO:0051604),
  protein processing/protein autoprocessing: ACCEPT the core ones.
• pyroptotic inflammatory response (GO:0070269): ACCEPT — core.
• positive regulation of interleukin-1 beta / -18 production (GO:0032731/GO:0032741):
  ACCEPT — core; CASP1 performs the maturation step that produces the active cytokine.
• pattern recognition receptor signaling pathway (GO:0002221, NAS): CASP1 is the effector
  protease downstream of PRRs, not itself a PRR; MODIFY to inflammasome-mediated signaling
  pathway (GO:0141084), which is the precise home.
• positive regulation of canonical NF-kappaB signal transduction (GO:0043123): indirect /
  context-specific (via RIP2, Mal/TIRAP cleavage); KEEP_AS_NON_CORE or MARK_AS_OVER_ANNOTATED.
• apoptotic process / positive/regulation of apoptotic process: real for overexpressed
  enzyme and disease models but pleiotropic/non-core; KEEP_AS_NON_CORE.
• icosanoid biosynthetic process (GO:0046456, NAS PMID:22902502): downstream physiological
  consequence; CASP1 does not catalyze eicosanoid synthesis → MARK_AS_OVER_ANNOTATED.
• osmosensory signaling pathway (GO:0007231, NAS PMID:22981536): CASP1 is activated by cell
  swelling via NLRP3; it does not do the osmosensing → MARK_AS_OVER_ANNOTATED.
• cellular response to mechanical stimulus (GO:0071260, IEP PMID:19593445): the cached paper
  is about BAD/prostate cancer; cannot verify a CASP1 mechanical-stimulus assay → UNDECIDED.
• microtubule (GO:0005874, NAS PMID:27911804): that paper is about pyrin and microtubules,
  not CASP1 localizing to microtubules → MARK_AS_OVER_ANNOTATED / UNDECIDED.
• nucleolus (GO:0005730, NAS PMID:28263976): that paper reports NLRP1 nucleolar localization,
  not CASP1 → MARK_AS_OVER_ANNOTATED.

Note on file provenance (merge from main)

CASP1-uniprot.txt and CASP1-goa.tsv were also fetched independently on main
(PR #4960) so that the GO:0050729 IDA rows cited in
modules/canonical_nlrp3_inflammasome.yaml (caspase-1 role_description) are
checkable from the repository. That branch carried a placeholder notes file stating
"no gene review yet"; it is superseded by this notes file and the review added here.